Project Summary Accumulation of cholesteryl esters (CE)-laden macrophage (M?) foam cells in the arterial intima is a hallmark of atherosclerotic plaque development that underlies cardiovascular diseases (CVD). Current therapies are primarily targeted at reducing the circulating plasma LDL-C levels either by reducing de novo cholesterol synthesis (by statins) or by reducing absorption of dietary cholesterol (by ezetimibe). However, despite attaining target plasma LDL-C levels, residual risk due to the burden of existing plaque still remains. Furthermore, the inherently inflammatory milieu of the plaque contributes to the vulnerability of the plaque that leads to acute events such as heart attacks and stroke. Recent advances have established the critical role of inadequate removal of cholesterol from the plaques and defective removal of apoptotic cells from the advancing plaques (i.e., reduced efferocytosis) as two very critical mechanisms for intra-plaque inflammation and vulnerability. Therefore, the long-term goal of this project is to develop novel strategies to effectively decrease the CE burden of existing plaques as well as to reduce plaque inflammation. Earlier studies from the PI's (Ghosh) laboratory have demonstrated that targeted reduction in M? CE accumulation not only reduced cholesterol content and size of the plaque but it also significantly reduced plaque associated inflammation resulting in reduced M? apoptosis and necrosis. It is also noteworthy that in contrast to directly targeting reduction in plaque inflammation using anti-inflammatory agents that will modulate only one risk factor, indirect modulation by reducing cellular cholesterol content achieves reduction of two critical risk factors, namely, CE levels as well as inflammation. However, one of the biggest challenges in such targeted modulation approaches is the availability of appropriate delivery platforms. Nanomedicines provide such a platform and working in close collaboration, the two PIs of this multi-PI proposal have developed mannose-functionalized polyamidoamine (PAMAM) dendrimer based nanoparticles (DNPs) to deliver agents characterized to beneficially modulate cellular functions specifically to M? via the mannose receptor and demonstrated in vivo efficacy in reducing atherosclerotic plaque burden/inflammation. We hypothesize that ?development of functionalized nanoparticles with an increased potential for uptake by macrophages and delivery of agents to enhance CE removal as well as modulate inflammation will facilitate or enhance the beneficial modulation of macrophage function.? This hypothesis will be tested by the following two Aims: Aim 1: Using a functionalized DNP platform, deliver agent(s) to enhance cholesterol mobilization from M? foam cells and simultaneously reduce plaque-associated inflammation. Aim 2: To establish the ability of functionalized DNPs to deliver enhancers of efferocytosis and effectively modulate this specific function of M?s. The successful completion of the proposed studies will lead to the development of novel dendrimeric nanoparticle based platform to reduce atherosclerosis/plaque regression.